Nonsteroidal and Steroidal Aromatase Inhibitors in Breast Cancer

Nonsteroidal and Steroidal Aromatase Inhibitors in Breast Cancer

Drs. Hamilton and Volm provide an excellent and concise
review of the use of aromatase inhibitors in the treatment of breast cancer.
There has been significant progress in hormonal therapy for this disease in the
past decade. In this review, the role of aromatase (a P450 enzyme) in the
production of estrogen and aromatase inhibitors in suppressing the production of
estrogen in postmenopausal women is well described.

The breast tissue and breast stroma have significant aromatase
activity, but the correlation between the aromatase activity in tumor or in
stromal tissue and the response to aromatase inhibitors have not been
established. In clinical practice, the presence of estrogen and progesterone
receptors still provides the best positive and negative correlations regarding
responses to all endocrine therapies, including aromatase inhibitors. Patients
whose tumors have both estrogen and progesterone receptors have a higher
probability of response, whereas those whose tumors lack both receptors have a
very low probability of response to any endocrine therapy and are better managed
by other treatment modalities.

Drs. Hamilton and Volm briefly discuss data from a small
study[1] that evaluated the inhibition of total-body aromatase activity and
suppression of estrogen production by two aromatase inhibitors. A washout period
between crossover phases was not part of this study design. In light of these
laboratory data, the authors’ implications that one aromatase inhibitor may be
superior are not justified: The estrone and estradiol levels were similarly
suppressed by the two agents, and the only significant change was in estrone
sulfate. Most other differences in estrogen suppression between the two drugs
were close to the current assay’s detection threshhold. Therefore, any
implications regarding a therapeutic benefit remain to be confirmed.

Two large databases (ie, for anastrozole [Arimidex] and
letrozole [Femara] studies) demonstrate that both of these newer aromatase
inhibitors are superior to tamoxifen (Nolvadex) as front-line therapy in
estrogen-receptor-positive patients. The data regarding exemestane (Aromasin)
are too preliminary to assess this agent’s antitumor activity compared with
tamoxifen.

Comparative Data

All three aromatase inhibitors available for clinical use have
substantial antitumor activity, but currently there are no prospective
randomized studies evaluating their antitumor activity in similar cohorts of the
patient population. Appropriate clinical comparative studies of these aromatase
inhibitors are needed to compare their therapeutic efficacy in a prospective
manner.

The indirect comparative data (from the available studies) of
these aromatase inhibitors in postmenopausal women are summarized in Table
1.
These analyses do not demonstrate major differences in either second- or
first-line settings. The differences between the letrozole and tamoxifen arms in
the letrozole front-line study were considerably larger than the differences
between anastrozole and tamoxifen in the anastrozole front-line study. This may
derive from the fact that, in the letrozole study, patients who had prior
tamoxifen therapy (> 18% of the total population) had a very low response
rate (8%) to tamoxifen re-treatment, whereas in the anastrozole study, no
significant differences were observed in response rates for patients who had
prior tamoxifen therapy.

All three drugs have been evaluated at different doses and, at
the present time, there are no convincing data regarding dose-dependent
responses with these drugs. Some letrozole studies have demonstrated that the
2.5-mg dose of the drug may have superior antitumor activity, compared with the
0.5-mg dose. Data from a subsequent, large prospective US study failed to
confirm these findings.[2] The detailed results of this study are currently in
the process of being published.[3]

Safety Profiles

The safety profiles of these agents are better than those of
earlier drugs (ie, progestins, aminoglutethimide [Cytadren], and tamoxifen), but
there are also subtle differences between these compounds. Anastrozole and
letrozole are triazole compounds, and anastrozole administered at up to 10-fold
the recommended dose does not cause any significant interference in the steroid
synthesis pathways,[4] but letrozole at a dose of 2.5 mg does show significant
blunting of adrenocorticotropic hormone response following 1 to 3 months of
therapy.[5]

Anastrozole and letrozole intrinsically do not have any hormonal
properties. On the other hand, exemestane is a steroidal compound with weak
androgenic properties, especially at higher doses. The implications of these
differences among the three drugs in the treatment of metastatic disease might
be difficult to evaluate at the present time. Prolonged administration of these
agents in the adjuvant setting, however, may reveal some of the differences in
their safety profiles.

The safety and efficacy data of a number of ongoing adjuvant
trials, as outlined in the article by Drs. Hamilton and Volm, would provide
information regarding the differences, if any, among these drugs. Appropriate,
direct comparative trials in front-line and/or adjuvant therapy would be the
best way to demonstrate any differences in the safety and efficacy of these
drugs.